To sustain vision, atRAL released from light-activated visual pigments, including rhodopsin, must be continuously isomerized back to its 11-cis isomer. This process occurs by a sequence of reactions catalyzed by membrane-bound enzymes of the retinoid cycle located in rod and cone photoreceptor outer segments and the retinal pigmented epithelium (RPE). Regeneration of rhodopsin requires 11-cis-retinal (11-cis-RAL) supplied from the RPE, but cone pigments are also regenerated in cone-dominant species by a separate “cone visual cycle”. A high flux of retinoids through the retinoid cycle, as occurs during intense light exposure, can cause elevated levels of toxic intermediates, especially atRAL, that can induce photoreceptor degeneration. Toxic effects of atRAL include caspase activation and mitochondrial-associated cell death, but the precise sequence of molecular events that leads to photoreceptor degeneration remains to be clarified.
Oxidative stress is one major mechanism contributing to photoreceptor cell death in animal models of retinal degeneration, including light-induced retinopathy. Tightly regulated low levels of reactive oxygen species (ROS) are needed to mediate physiological functions including cell survival, growth, differentiation and metabolism. NADPH oxidase is the primary enzymatic source of O2− and H2O2 involved in retinal degeneration. atRAL stimulates the production of reactive oxygen species superoxide via NADPH oxidase, however such stimulation does not result from a direct interaction between atRAL and this enzyme. Effective compositions and methods to reduce and minimize the production and release of ROSs in patients suffering from a variety of disparate ocular disorders would be a great boon to medicine and serve to reduce and eliminate a substantial amount of human suffering.